Development of new antibiotics simultaneously targeting beta-lactamases and penicillin-binding proteins
01. October 2022 - 30. September 2024
1.04 Natural Sciences and mathematics/Chemistry
β-Lactam antibiotics remain the single most important antibiotic class in use worldwide. The clinical longevity of β-lactams is threatened by bacterial resistance enzymes (i.e. β-lactamases, BL) that can inactivate them by hydrolysis. We face a growing resistance to Gram-positive and Gram-negative pathogens that cause infections in hospitals and the community, with the so-called antibiotic-resistant ‘superbugs’ that now represent a major global health problem. There is therefore an urgent need for medicinal chemists to develop new antibacterial lead compounds with improved biological properties, that can bind to validated antibacterial targets (such as the penicillin-binding proteins, PBPs). Bicyclic boronates (BCBs) are emerging as a promising scaffold for broad-spectrum inhibition of BLs, which are the most clinically relevant determinant of resistance to β-lactam antibiotics in Gram-negative organisms. BCBs are very broad-spectrum BL inhibitors and have considerable clinical potential, having inhibitory activity against both serine- and metallo-BLs (SBLs and MBLs, respectively). During this Project, we aim to discover and develop new types of antibiotics with simultaneous inhibitory activity against MBLs and PBPs (and SBLs). We try to achieve this by preparing structurally innovative β-lactam analogues that will contain structural elements of the promising BCB pharmacophore. Fragment- and/or structure-based design will be used to generate ideas on how to improve and grow our compounds, and the improved analogues will then be prepared. Accessing such complex compounds is a challenging task and is often hindered by synthetic impracticality. However, when experience and specific know-how in the multi-step asymmetric synthesis that the postdoctoral researcher has acquired in the past is joined with complementary long-term experiences in design, synthesis and biological evaluation of bioactive leads from the host department, this represents a strong foundation for successful realization of this innovative project. All target compounds and interesting intermediates will be pharmacologically evaluated. The work will be iterative and will proceed in a typical drug discovery iterative loop consisting of design, synthesis, biochemical evaluation, and structural evaluation, where the latter will be used to start new development iteration using cutting-edge chemical synthesis. The results of the proposed project will therefore represent an important contribution to the cause of AMR. The Project is executed in collaboration with partners from Slovenia and abroad. Together, we advance the following approaches and tools relevant for the continuous development of the pharmaceutical and chemical sciences: structure-based drug discovery, fragment-based drug design, asymmetric organic synthesis and optimization of lead compounds and synthetic organic methodology. Our research will primarily focus on the use of the listed tools for the successful discovery of novel antibacterial agents with new modes of action. A scientific breakthrough in this area has the potential, to solve the problem of the emergence of resistant bacterial strains and greatly reduce the number of deaths caused by the growing number of infections with superbugs. The growing prevalence of antibiotic resistance, in particular as manifested in carbapenem-resistant Gram-negative bacteria, makes the development of PBP inhibitors able to resist the activity of clinically relevant β-lactamase classes an urgent clinical need. The combined results will thus represent a significant contribution to the development of new antibacterials that can potentially simultaneously target PBPs and β-lactamases, or at the very least provide the basis for the development of new generations of antibacterial agents. The current research team provides the necessary drive, vision and complementary expertise to achieve the outlined research goals.
Bibliographical references, arising directly from the implementation of the project:
Research projects (co)funded by the Slovenian Research Agency.
Changed: 05. May 2023